The molecular and cellular mechanism involved in the etiology of Alzheimer?s disease (AD) is still not fully understood. The risk factors underlying the heterogeneity and multifactorial nature of AD may include genetic background, environment, life styles, and the status of key molecules, i.e. amyloid, tau, ApoE, TREM2, biometals (Ca2+, Mg2+, Cu2+, etc.) and others. The goal of this study is to explore the potential role of Mg2+ in neuronal cell protection under AD-like pathological conditions and the underlying molecular mechanisms. The rationale is that 1) Mg2+-deficiency is correlated to aging and AD pathology, and 2) elevated brain Mg2+ enhances learning and memory, reduces neuroinflammation, and protects cognitive functions and synaptic plasticity in AD animal models. Prior studies revealed that brain and serum Mg2+ levels are significantly lower in patients with AD than in age-matched normal subjects. Moreover, Mg2+ elevation enhanced learning and memory in aged rats, prevented synaptic loss and reversed cognitive deficits in APP/PS1 AD mice and streptozotocin-induced sporadic AD rat model, as well as reduced neuroinflammation in brain injury and APP/PS1 AD model. In light of these findings, dyshomeostasis of Mg2+ in the brain is believed to be involved in the progression of AD. In addition, Mg2+ itself is a nature antioxidant, an antagonist of Ca2+, and an essential cofactor for ATP, nucleic acids and over 600 enzyme systems. Thus collectively, the hypothesis is that Mg2+ protects neurons by serving as an antioxidant to reduce oxidative stress, inflammation, and synaptic loss. Aim 1 is to examine efficacy and mechanism of Mg2+ on reducing oxidative stress and neuroinflammation. Aim 2 is to examine efficacy and mechanism of Mg2+ on inhibiting A?-induced synaptic loss and dysfunction. First, the mechanisms of how Mg2+ enters the cells and reduces A?-induced oxidative stress and inflammation in vitro will be elucidated and followed by validation of its efficacy on oxidative stress & inflammation suppression in AD animal model. Next, the mechanisms of how Mg2+ protects neurons from A?-induced synaptic loss and dysfunction, as well as A?- induced tau hyperphosphorylation and mitochondrial fragmentation in vitro. Last, the efficacy of Mg2+ on synaptic plasticity and cognitive deficits amelioration in AD animal model will be validated.